There are two populations of liver sinusoidal endothelial cell (LSEC) progenitor cells. The LSEC progenitor cells in the bone marrow play an important role in repair of liver injury and promoting liver regeneration, but play no role in norml turnover. The LSEC progenitor cells in the liver (resident LSEC progenitor cells) contribute much less to repair of liver injury and promoting liver regeneration, but are the progenitors for normal LSEC turnover. The overarching objective of this proposal is to elucidate mechanisms underlying dysfunction of LSEC progenitor cells and of progenitor cell repair with the goal of identifying therapeutic targets. Specific aim 1 is based on the hypothesis that regulation of recruitment of bone marrow LSEC progenitor cells (i.e. proliferation of LSEC progenitors in the bone marrow, mobilization of progenitors from bone marrow to the circulation, and engraftment in the liver) is impaired in chronic liver disease and that this impairment of a repair process increases the damage of acute liver injury and impairs liver regeneration in chronic liver disease. Studies will examine the effect of acute injury in chronic liver disease on bone marrow LSEC progenitor cell recruitment to the liver, establish predictors for the risk of inadequate progenitor cell recruitment, and determine whether acute injury is attenuated with progenitor cell therapy. The hypothesis for specific aim 2 is that acute liver injury alters the signaling pathways for bone marrow LSEC progenitor cell engraftment in the liver. Studies will examine the effect of altered signaling on bone marrow LSEC progenitor cell engraftment and on liver regeneration, elucidate the mechanisms that lead to the impairment of signaling, and will determine whether strategies to restore normal signaling ameliorate acute injury. The hypothesis for the third aim is that phenotypic changes in LSEC with aging are due to changes in resident progenitor cells. Studies will determine whether the changes in the LSEC are indeed due to changes in the progenitor cell and will examine the signaling pathways that lead to the changes in the resident progenitor cells.